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Author Spotlight: Establishing MASLD Cell Models for Investigating Disease Mechanisms and the Lipid-Lowering Effects of Koumiss
Published on: July 19, 2024
Rapamycin ameliorates intrahepatic inflammation in MASLD by increasing macrophage fatty acid oxidation levels
Xiaonan Du1, Xiaotong Han2, Jingjing Zhu2
1Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
Abstract:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver disease and a serious threat to public health. Mammalian target of rapamycin (mTOR) plays an important role in the progression of MASLD and can be a potential therapeutic target. Our data show that rapamycin treatment can alleviate MASLD symptoms, including liver inflammation, steatosis and steatohepatitis, in the WD, CDHFD- or MCD-induced MASLD mouse model, but has no significant effect on hepatic fibrosis. Analysis of the liver immune microenvironment revealed that rapamycin mainly inhibited the inflammatory response of bone marrow-derived macrophages. Moreover, transcriptome sequencing of these macrophages in the livers of MASLD mice treated with or without rapamycin revealed that rapamycin reduced bone marrow-derived macrophage activation and proinflammatory effects. We demonstrated that rapamycin exerts its protective effect mainly by increasing the fatty acid oxidation (FAO) level of macrophages and decreasing their proinflammatory ability during MASLD development, which may provide new ideas for the intervention and treatment of MASLD and MASH.
Insights
Rapamycin alleviates metabolic dysfunction-associated steatotic liver disease (MASLD) by reducing liver inflammation and steatosis. This mTOR inhibitor targets macrophages, enhancing fatty acid oxidation and decreasing inflammatory responses, offering new therapeutic avenues for MASLD and MASH.
Area of Science:
- Hepatology
- Immunology
- Metabolic Diseases
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent condition with significant public health implications.
- Mammalian target of rapamycin (mTOR) signaling is implicated in MASLD progression and represents a potential therapeutic target.
- Current therapeutic strategies for MASLD and metabolic steatohepatitis (MASH) require further development.
Purpose of the Study:
- To investigate the therapeutic potential of rapamycin in MASLD mouse models.
- To elucidate the mechanisms by which rapamycin impacts the liver immune microenvironment in MASLD.
- To assess the effect of rapamycin on macrophage activation and function during MASLD.
Main Methods:
- Establishment of MASLD mouse models using specific dietary interventions (WD, CDHFD, MCD).
- Administration of rapamycin to assess its effects on liver steatosis, inflammation, and fibrosis.
- Analysis of the liver immune microenvironment, focusing on bone marrow-derived macrophages.
- Transcriptome sequencing of macrophages to identify molecular changes induced by rapamycin.
Main Results:
- Rapamycin treatment significantly alleviated MASLD symptoms, including liver inflammation and steatosis, but did not impact hepatic fibrosis.
- Rapamycin primarily inhibited the inflammatory response of bone marrow-derived macrophages within the liver.
- Transcriptome analysis revealed that rapamycin reduced macrophage activation and proinflammatory cytokine production.
- Rapamycin enhanced fatty acid oxidation (FAO) in macrophages and diminished their proinflammatory capacity.
Conclusions:
- Rapamycin demonstrates a protective effect against MASLD by modulating macrophage function.
- The mechanism involves increasing macrophage fatty acid oxidation and reducing their pro-inflammatory state.
- These findings suggest rapamycin as a potential therapeutic agent for MASLD and MASH, offering novel intervention strategies.
